Inhaler

ABSTRACT

An inhaler is disclosed. It comprises a housing to receive a strip having a plurality of blisters, each blister having a breachable lid and containing a dose of medicament for inhalation by a user, an indexing wheel mounted in the housing rotatable to drive a strip to sequentially move blisters into alignment with a blister piercing member, a control element pivotally mounted to the housing and a drive mechanism configured to couple the control element to the indexing wheel during part of the rotation of the control element by a user so that the indexing wheel rotates together with the control element.

This application is a U.S. national phase application under U.S.C. §371of International Application No. PCT/EP2009/050344, filed Jan. 14, 2009,which claims priority to European Patent Application No. EP08100892.2,filed Jan. 24, 2008, the disclosures of which are hereby incorporated byreference in their entirety.

The present invention relates to an inhalation device for oral or nasaldelivery of medicament in powdered form. More specifically, theinvention relates to an inhaler having a housing to receive a striphaving a plurality of blisters spaced along the length of the strip,each blister having a puncturable lid and containing a dose ofmedicament for inhalation by a user. The invention also relates to aninhaler containing a strip of blisters each having a puncturable lid andcontaining a dose of medicament for inhalation by a user of the deviceaccording to the invention.

Oral or nasal delivery of a medicament using an inhalation device is aparticularly attractive method of drug administration as these devicesare relatively easy for a patient to use discreetly and in public. Aswell as delivering medicament to treat local diseases of the airway andother respiratory problems, they have more recently also been used todeliver drugs to the bloodstream via the lungs, thereby avoiding theneed for hypodermic injections.

It is common for dry powder formulations to be pre-packaged inindividual doses, usually in the form of capsules or blisters which eachcontain a single dose of the powder which has been accurately andconsistently measured. A blister is generally cold formed from a ductilefoil laminate or a plastics material and includes a puncturable lidwhich is permanently heat-sealed around the periphery of the blisterduring manufacture and after the dose has been introduced into theblister. A foil blister is preferred over capsules as each dose isprotected from the ingress of water and penetration of gases such asoxygen in addition to being shielded from light and UV radiation all ofwhich can have a detrimental effect on the delivery characteristics ofthe inhaler if a dose becomes exposed to them. Therefore, a blisteroffers excellent environmental protection to each individual drug dose.

Inhalation devices that receive a blister pack comprising a number ofblisters each of which contain a pre-metered and individually packageddose of the drug to be delivered are known. Actuation of the devicecauses a mechanism to breach or rupture a blister, such as by puncturingit or peeling the lid off, so that when the patient inhales, air isdrawn through the blister entraining the dose therein that is thencarried out of the blister through the device and via the patient'sairway down into the lungs. Pressurized air or gas or other propellantsmay also be used to carry the dose out of the blister. Alternatively,the mechanism that punctures or opens the blister may push or eject thedose out of the blister into a receptacle from which the dose maysubsequently be inhaled.

It is advantageous for the inhaler to be capable of holding a number ofdoses to enable it to be used repeatedly over a period of time withoutthe requirement to open and/or insert a blister into the device eachtime it is used. Therefore, many conventional devices include means forstoring a number of blisters each containing an individual dose ofmedicament. When a dose is to be inhaled, an indexing mechanism moves apreviously emptied blister away from the opening mechanism so that afresh one is moved into a position ready to be opened for inhalation ofits contents.

An inhaler of the type described above is known from the Applicant's ownco-pending international application no. PCT/GB2004/004416 filed on 18Oct. 2004 and claiming priority from GB0324358.1 filed 17 Oct. 2003.This international application has been published as WO2005/037353 A1.

According to one embodiment described and claimed in WO 2005/037353 A1,and illustrated in FIGS. 1 and 2 of the accompanying drawings, aninhaler 1 has a housing 2 containing a coiled strip 3. The strip 3 has aplurality of individually spaced moisture proof blisters each containinga pre-measured dose of powdered medicament for inhalation. Each blisterof the strip comprises a generally hemispherically shaped pocket and aflat puncturable lid permanently heat sealed to the pocket tohermetically seal the dose therein. The strip is preferably manufacturedfrom foil laminate or a combination of foil laminate, such as aluminium,and plastics material.

An indexing mechanism 4 comprising a single actuating lever 5 unwindsthe coil 3 one blister at a time so that they pass over a blisterlocating chassis 6 and successively through a blister piercing station7, when the actuator 5 is pivoted in a direction indicated by arrow “A”in FIG. 2. The blister 3 a located at the blister piercing station 7 oneach movement of the actuator 5 is pierced on the return stroke of theactuator 5 (in the direction indicated by arrow “B” in FIG. 2) bypiercing elements 8 on the actuator 5 itself so that, when a userinhales through a mouthpiece 9, an airflow is generated within theblister 3 a to entrain the dose contained therein and carry it out ofthe blister 3 a via the mouthpiece 9 and into the user's airway.

In another embodiment disclosed in WO2005/037353 A1, indexing andpiercing of a blister positioned at the blister piercing station 7 iscarried out in response to rotation of a cap that covers the mouthpiecein a closed position, rather than as a result of direct rotation of theactuator by the user.

Each of the devices disclosed in WO2005/037353 A1 have a drive mechanismthat includes an indexing wheel. A blister strip passes over theindexing wheel and the wheel rotates in response to pivotal movement ofan acutator or cap so as to drive or index the strip through the device.The drive mechanism is configured such that the indexing wheel rotatesin response to rotation of the actuator or cap in one direction butremains stationary when the actuator or cap is rotated in the oppositedirection.

The present invention seeks to provide an alternative an inhaler havingan improved drive mechanism for coupling the actuator, or cap, to theindexing wheel so that rotation of the indexing wheel occurs duringrotation of the cap or actuator in one direction. However, the inventionalso seeks to provide a modified drive mechanism in which the indexingwheel will rotate during only part of the movement of the actuator orcap in the same direction. In particular, the indexing wheel will rotateto index a strip during a first part of the movement of the actuator orcap in one direction and, when the actuator or cap has reached anintermediate position, the actuator or cap will disengage from theindexing wheel so that, during further movement of the actuator or capin the same direction beyond the intermediate position, no furtherrotation of the indexing wheel will occur.

In a cap operated device in which a cap, which normally covers themouthpiece in a closed position, is pivoted to index a strip and also tomove an actuator to cause a piercing element mounted to or associatedwith the actuator to puncture the lid of a blister, the drive mechanismmay be configured such that a fresh blister may be located in alignmentwith the blister piercing member when the intermediate position of thecap has been reached so that further movement of the cap in the samedirection beyond the intermediate position causes the blister piercingmember to pierce the pre-aligned and stationary blister.

According to the invention, there is provided an inhaler comprising ahousing to receive a strip having a plurality of blisters, each blisterhaving a breachable lid and containing a dose of medicament forinhalation by a user, an indexing wheel mounted in the housing rotatableto drive a strip to sequentially move blisters into alignment with ablister piercing member, a control element pivotally mounted to thehousing and a drive mechanism configured to couple the control elementto the indexing wheel during part of the rotation of the control elementby a user so that the indexing wheel rotates together with the controlelement.

Preferably, the control element rotates relative to the housing about anaxis and the drive mechanism comprises a coupling member in the housingfor rotation about the same axis. Although the control element andcoupling member preferably rotate about the same axis, it is alsoenvisaged that they may rotate about separate axes that are offset fromeach other.

In a preferred embodiment, the control element and coupling member areconnected so that they rotate together.

The indexing wheel may be rotatably mounted to the coupling member.

In a preferred embodiment, the coupling member includes a shaft havingan axis coaxial with the axis of the control element, the indexing wheelbeing mounted on said shaft for rotation about said axis.

In one embodiment, the coupling member comprises an indexing wheel drivedog and the drive mechanism includes means to move, as the controlelement and coupling member are rotated, the indexing wheel drive doginto a position in which it cooperates with the indexing wheel so thatthe indexing wheel rotates together with the control element and thecoupling member.

The coupling member is preferably formed from a resilient material andsaid means for moving the indexing wheel drive dog into a position inwhich it cooperates with the indexing wheel moves said indexing wheeldrive dog against a bias provided by said resilience.

The coupling member may comprise a flange that extends radially from oneend of the shaft across one end of the indexing wheel. Preferably, theflange lies in a plane extending substantially at right-angles to theaxis of the shaft.

In one preferred embodiment, the flange includes a flexible flangeportion that resiliently bends or flexes relative to the remainingportion of the flange about an axis extending substantially at rightangles to the axis of the shaft.

The flange may have a cut-out region configured such that the flexibleflange portion is joined only to the remaining portion of the flange toa limited extent.

In one embodiment, the flexible flange portion is hinged to theremaining portion of the flange at each end.

Conveniently, the indexing wheel drive dog upstands from a surface ofthe flexible flange portion in a direction towards the indexing wheel.

Preferably, the means to move the indexing wheel drive dog into aposition in which it cooperates with the indexing wheel so that theindexing wheel rotates together with the control element comprises acoupling member deflecting dog protruding from the flexible flangeportion.

In a preferred embodiment, the means to move the indexing wheel drivedog into a position in which it cooperates with the indexing wheel alsocomprises an arcuate guide track in the housing, the arcuate guide trackhaving a first guide surface such that, when the coupling member isrotated in response to rotation of the control element in a firstdirection, the coupling member deflecting dog cooperates with the firstguide surface to deflect the flexible flange portion towards theindexing wheel so that the indexing wheel drive dog cooperates with theindexing wheel to rotate the indexing wheel together with the couplingmember.

The arcuate guide track is advantageously configured such that thecoupling member deflecting dog drops off the first guide surface priorto rotation of the control element to its maximum extent, the resilienceof the flexible flange portion causing it to return to its originalundeflected state so that the indexing wheel drive dog no longercooperates with the indexing wheel, the indexing wheel now remainingstationary during continued rotation of the control element and couplingmember to its maximum extent.

The arcuate guide track preferably comprises a second guide surface suchthat, when the flange portion deflecting dog has dropped off the firstguide surface and the coupling member is rotated in response to rotationof the control element in a reverse direction, the flange portiondeflecting dog cooperates with said second guide surface so that theflexible flange portion is deflected in the opposite direction, awayfrom the indexing wheel, so that the indexing wheel drive dog does notcooperate with the indexing wheel and the indexing wheel remainsstationary.

The coupling member deflecting dog preferably comprises a firstcooperating surface to engage the first guide surface of the arcuateguide track, and, a second cooperating surface to engage the secondguide surface of the arcuate guide track.

The first and second guide surfaces of the arcuate guide track mayextend parallel to each other but spaced from each other in an axialdirection.

Ideally, the first and second guide surfaces have angled end regionssuch that the coupling member deflecting dog rides up the angled endregions onto respective guide surfaces.

In a preferred embodiment, the indexing wheel comprises a plurality ofvanes and the indexing wheel drive dog contacts one of the vanes whenthe indexing wheel drive dog is moved into a position in which itcooperates with the indexing wheel so that the indexing wheel rotatestogether with the coupling member and the control element.

In a preferred embodiment, the inhaler comprises a locking element toprevent rotation of the indexing wheel other than during cooperation ofthe indexing wheel drive dog with the indexing wheel.

In this embodiment, the locking element preferably comprises acantilevered arm mounted in the housing and having its free end biasedagainst the indexing wheel, said free end of the cantilever armcooperating with the indexing wheel so as to prevent rotation of theindexing wheel.

The free end of the cantilevered arm may be configured such that whenthe indexing wheel drive dog is moved towards the indexing wheel,further rotation of the coupling element causes the indexing wheel drivedog to engage the free end of the cantilever arm and deflect it out oflocking engagement with the indexing wheel prior to cooperating with theindexing wheel to rotate the indexing wheel.

Preferably, the indexing wheel drive dog disengages the free end of thecantilever arm when the indexing wheel drive dog moves away from theindexing wheel so that the free end of the cantilever arm moves backtowards the indexing wheel to lock the indexing wheel in position.

Preferably, the indexing wheel comprises a plurality of vanes and thefree end of the cantilever arm comprises a slot, the slot beingconfigured to receive a tip of a vane when the free end of thecantilever arm is biased against the indexing wheel to lock the indexingwheel in position.

Each vane may comprise an enlarged head portion and the slot in the freeend of the cantilever arm is configured to receive said enlarged headportion.

Conveniently, the inhaler may comprise a chassis to locate a blisterstrip as it moves therethrough and the cantilever arm extends from saidchassis.

According to another aspect, there is provided an inhaler according tothe invention comprising a coiled strip of blisters received within thehousing and passing around the indexing wheel.

Embodiments of the invention will now be described, by way of exampleonly, with reference to FIGS. 3 to 8 of the accompanying drawings, inwhich:

FIGS. 1 and 2 are side views of a prior art inhalation device to showhow a strip is driven to sequentially move blisters into alignment witha blister piercing element by movement of an actuator from the positionshown in FIG. 1 to the position shown in FIG. 2 which drives an indexingwheel. A piercing head on the actuator pierces the lid of an alignedblister when the actuator is returned to its normal position, as shownin FIG. 1;

FIG. 3 is a partial perspective view of an inhaler according to thepresent invention incorporating an improved blister strip indexingmechanism, with the actuator in its home, stowed or locked positionprior to use of the inhaler;

FIG. 4 is a partial perspective view of the inhaler shown in FIG. 3 inwhich the actuator has been rotated into an intermediate position fromits home position;

FIG. 5 is the same view as shown in FIG. 4, but with the cantileveredchassis arm omitted for clarity;

FIG. 6 is a partial perspective view of the inhaler shown in FIGS. 1 to5, after the actuator has been rotated to a point at which drive betweenthe drive coupling and the actuator has disengaged;

FIG. 7 is a partial perspective view of the opposite side of the inhalershown in FIGS. 1 to 6;

FIG. 8 a is a perspective view of the drive coupling used in theindexing mechanism of the inhalers shown in FIGS. 1 to 7; and

FIG. 8 b is a side view of the drive coupling illustrated in FIG. 8 a inwhich the flexible flange portion has been deflected in a direction “T”towards the shaft or, towards an indexing wheel mounted on that shaft.

The drive mechanism of the present invention will now be described indetail with reference to FIGS. 3 to 8. It will be appreciated that thisdrive mechanism may be used in the inhaler described above withreference to FIGS. 1 and 2 but may also be used in other blister stripinhalation devices. In particular, it can also be used in a blisterstrip inhalation device in which a cap, which covers the mouthpiece in aclosed position, is rotated to index the strip and in which an actuatoris operable, either separately or in response to rotation of the cap tocause a blister piercing member to pierce the lid of an aligned blister.It may also be used in devices in which the used blisters are retainedwithin the device.

Therefore, although the following description primarily makes referenceto an embodiment in which the actuator is rotated to index the strip,such as the actuator 5 of FIGS. 1 and 2, any control element isconsidered to fall within the scope of the invention, such as a “cap”that covers the mouthpiece and which is coupled to a separate actuator.

Referring now to FIG. 3, there is shown a partial perspective view of aninhalation device 10 comprising an indexing mechanism 11 according to anembodiment of the present invention. It will be appreciated that partsof the housing 12 and internal components such as the blister locatingchassis 13 and actuator 14 are only partially shown for the purposes ofclarity and ease of understanding.

The indexing mechanism 11 includes an indexing wheel 15 comprising fourvanes 15 a,15 b,15 c,15 d, each having an enlarged head portion 16 a,16b,16 c,16 d. As is clear from reference to FIGS. 1 and 2, once a blisterstrip (not shown in FIGS. 3 to 8) has passed over the blister locationchassis 13, it passes around the indexing wheel 15. A blister locates inthe space between two vanes 15 a,15 b,15 c,15 d so that, as the indexingwheel 15 rotates in response to rotation of the actuator 14, a vane 15a,15 b,15 c,15 d engages a blister located between the vanes 15 a,15b,15 c,15 d so as to drive the strip around the indexing wheel 15 tosequentially move each blister forward by a sufficient distance to movea fresh blister into alignment with a blister piercing element (notshown in FIGS. 3 to 8).

The indexing mechanism 11 includes a drive coupling member 17 (mostclearly shown in FIGS. 8 a and 8 b) for selectively or temporarilycoupling the actuator 14 to the indexing wheel 15 so that, when coupled,the indexing wheel 15 rotates in response to rotation of the actuator 14to index the strip. The drive coupling member 17 comprises a shaft 18defining an axis of rotation “A” (see FIGS. 8 a and 8 b) on which theindexing wheel 15 is rotatably received so that it can rotate freelyabout the shaft 18 about said axis of rotation “A”. The actuator 14 isfixedly attached to the drive coupling member 17 (such as by a splinedpin—not shown)—that is inserted through the actuator 14, through anaperture 12 a (see FIG. 7) in the housing 12 and is received within theopening 18 a in the shaft 18) so that the drive coupling member 17rotates together with the actuator 14 at all times. The actuator 14,drive coupling member 17 and indexing wheel 15 are all mounted coaxiallyfor rotation about the same axis “A”.

The drive coupling member 17 has a circular flange 19 that extendsradially from one end of the shaft 18. A portion 20 of the flange iscut-away (see arcuate opening 21 in FIG. 8) over an angle ofapproximately 180 degrees where the flange 19 joins the shaft 18 so thatthis portion 20 of the flange 19 is not directly attached to the shaft18 but only to the remaining portion of the flange 19 at each of itsends 20 a,20 b. As a result, this portion 20 of the flange 19 isflexible relative to the rest of the flange 19 and can be deflected outof the plane of the flange 19 that extends at right angles to the axisof the shaft, in an axial direction (indicated by “T” and “S”, in FIG. 8and FIG. 8 b) either towards or away from the shaft 18 or, moreimportantly, towards or away from the indexing wheel 15 which is mountedon the shaft 18, when force is applied to it. This flexible flangeportion 20 hinges about an axis B which intersects the axis A of theshaft 18 and actuator 14 but extends at right angles to it. The drivecoupling member 17, or at least the flange 19, is made from a resilientmaterial so that when the deflected flexible flange portion 20 isreleased, it returns to its neutral, unstressed position, in which itlies coplanar with the remaining fixed portion of the flange 19.

The flexible flange portion 20 has an integrally formed flangedeflecting dog 22 projecting radially from its circumferential edge. Theflange deflecting dog 22 has first and second angled engaging faces23,24 on opposite sides. When the drive coupling member 17 is rotated inresponse to rotation of the actuator 14 in one direction, one of thefirst or second angled engaging faces 23,24 cooperate with a fixedformation 25 on the housing 12 to cause the flexible flange portion 20to deflect in a first direction. When the drive coupling member 17 isrotated in the opposite direction, the other angled engaging facecooperates with the formation 25 on the housing 12 to cause the flexibleflange portion 20 to deflect in a second, opposite direction, as will beexplained in more detail below.

The flexible flange portion 20 also has an arcuately shaped indexingwheel drive dog 26 that upstands in an axial direction from its surfacetowards the indexing wheel 15 in the same direction as the shaft 18 andextends partially around the circumference of the flexible flangeportion 20. As will now be explained in more detail below, an end face26 a (see FIG. 8 a) of the indexing wheel drive dog 26 engages a vane 15a,15 b,15 c,15 d of the indexing wheel 15 when the flexible flangeportion 20 has been deflected in a first direction, as indicated byarrow “T” in FIG. 8 b (the flange portion 20 is shown in its deflectedposition in FIG. 8 b), so that the indexing wheel 15 is driven togetherwith the drive coupling member 17.

As mentioned above, the flange deflecting dog 22 engages a formation 25on the housing 12 when the drive coupling member rotates in response torotation of the actuator 14 so as to flex the deflectable portion 20 ofthe flange 19. This formation 25 comprises first and second arcuatelyshaped tracks or paths 27, 28 positioned one above the other or spacedfrom each other in the axial direction. The surface of the innermosttrack 27 is visible in FIG. 1. The lower or outermost track 28 islocated beneath it and is visible in FIG. 7. The ends of the tracks 27a, 28 a have angled faces for reasons that will become apparent.

When the actuator 14 is rotated in a first direction (the directionindicated by arrow “A” in FIG. 3), the drive coupling member 17 rotatestogether with it and the first outwardly facing angled surface 23 on theflange deflecting dog 22 contacts the angled face 27 a of the innermosttrack 27. Further rotation of the drive coupling member 17 causes theflange deflecting dog 22 to ride up onto the surface of the innermosttrack 27 thereby deflecting the flexible flange portion 20 inwardly,i.e. in a direction into the housing 12 or towards the shaft 18 and theindexing wheel 15 and the direction indicated by arrow “T” in FIG. 8 b.

When the flexible flange portion 20 has been deflected inwardly in thedirection of arrow T, further rotation of the drive coupling member 17causes the indexing wheel drive dog 26 to engage a vane, which as shownin FIG. 1 is vane 15 c, of the indexing wheel 15 so that the indexingwheel 15 rotates together with the drive coupling member 17 and drive tothe indexing wheel 15 is engaged.

When the end of the innermost track 27 has been reached, the flangedeflecting dog 22 falls off the surface of the track 27 and theresilience of the flexible flange portion 20 causes it to return to itsoriginal unstressed or neutral position. When the drive coupling member17 is rotated further, the indexing wheel drive dog 26 no longer engageswith the vane 15 c of the indexing wheel 15 and instead passes beneathit so the indexing wheel 15 remains stationary. Therefore, drive to theindexing wheel 15 is disengaged, despite continued rotation of theactuator 14 in the same direction.

When the actuator 14 is rotated back in the opposite direction towardsits home position, the second inwardly facing angled surface 24 of theflange deflecting dog 22 now contacts the lower or outermost track 28 sothat the flange deflecting dog 22 now rides onto the surface of thatsecond track 28, thereby causing the flexible flange portion 20 todeflect outwardly or in the opposite direction to the direction in whichit was previously deflected, i.e in the direction indicated by arrowmarked “S” in FIG. 8 b. Engagement of the flange deflecting dog 22 withthe outermost track 28 so as to deflect the flange portion 20 in theopposite direction, enables the drive coupling member 17 to rotate inthe opposite direction without any drive to the indexing wheel 15. Itwill be appreciated that, if the flange portion 20 was not deflected inthe opposite direction, the flange deflecting dog 22 would simply engageagainst the end of the formation 25 in the housing 12 when rotated backin the opposite direction, thereby preventing rotation in the oppositedirection or, the flange deflecting dog 22 would travel back over theinnermost track 27 deflecting the flexible flange portion 20 in the samedirection causing the opposite end 26 b of the indexing wheel drive dog26 to engage with a vane 15 b of the indexing wheel 15 thereby drivingthe indexing wheel 15 backwards rather than leaving it stationary withno drive engaged. Therefore, it is necessary to ensure that the flexibleflange portion 20 is deflected in the opposite direction, i.e. in thedirection of arrow “S” in FIG. 8 a, so that there is no drive to theindexing wheel during rotation of the coupling member 17 in the oppositedirection.

When the drive deflecting dog 22 reaches the end of the outermost track28, the flexible flange portion 20 returns to its original unstressed orneutral position, due to its resilience.

In a preferred embodiment, the indexing mechanism 11 also includes meansfor locking the indexing wheel 15 to prevent its rotation betweenindexing steps and means for temporarily releasing that lock to allowrotation of the indexing wheel 15 when driven by the indexing wheeldrive dog 26. The lock also improves positional accuracy of the stripand, more specifically, the next blister to be pierced. This lockingarrangement will now be described in more detail below.

The blister location chassis 13 comprises a resiliently flexiblecantilever arm 30 that extends from the body 13 of the chassis towardsthe indexing wheel 15. The free end of the cantilever arm 30 has anenlarged head portion 31 comprising a letterbox shaped slot, window oropening 32 in which the head 16 c of a vane 15 c of the indexing wheel15 is located. The opening 32 is dimensioned such that the head 16 c ofthe vane 15 c (as shown in FIG. 1) is a snug fit therein so thatrotation of the indexing wheel 15 is prevented. In the normal or homeposition of the actuator 14, the head 16 c of a vane 15 c is located insaid opening 32 in the cantilever arm 30 of the chassis 13 so thatrotation of the indexing wheel 15 is prevented.

When the actuator 14 is rotated and the flange drive dog 22 engages theinnermost track 27 so as to deflect the flexible portion of the flange20 inwardly towards the indexing wheel 15, the indexing wheel drive dog26 initially engages with a protrusion 31 a from the enlarged head 31 onthe cantilever arm 30 of the chassis 13 so that the cantilever arm 30 isdeflected outwardly, away from the indexing wheel 15, to free the head16 c of the vane 15 c from the slot 32, thereby unlocking the indexingwheel 15. Only once the indexing wheel 15 has been released by theindexing wheel drive dog 26 pushing the cantilever arm 30 away from theindexing wheel 15 does the indexing wheel drive dog 26 subsequentlyengage a vane 15 c of the indexing wheel 15 so that further rotation ofthe drive coupling member 17 rotates the indexing wheel 15.

Prior to the flange drive dog 22 falling off the end of the innermosttrack 28 and the flexible flange portion 20 returning to its undeflectedstate due to its resilience, the indexing wheel drive dog 26 no longerpushes against the cantilever arm 30 and so the cantilever arm 30 isfree to move back towards the indexing wheel 15. As the cantilever arm30 is free to move back just prior to rotation of the indexing wheel 15being completed, the cantilever arm is prevented from moving all the wayback by the head 16 b of a following vane 15 b which contacts thecantilever arm 30. During further rotation of the indexing wheel, thehead 16 b slides across the cantilever arm and then drops into theopening 32 thereby allowing the cantilever arm 30 to move all the wayback and locking the indexing wheel 15 in position prior to any furtherrotation of the drive coupling member 17 in response to continuedrotation of the actuator 14.

On the return stroke of the actuator 14, it will be appreciated thatdeflection of the flexible flange portion 20 in the opposite direction,i.e. in a direction away from the indexing wheel and in the directionindicated by arrow “S” in FIG. 8 b, also ensures that the indexing wheeldrive dog 26 clears the chassis arm 30 and so the indexing wheel 15 isnot unlocked, thereby preventing any rotation of the indexing wheel 15during the return stroke.

It will be appreciated that the extent of rotation of the indexing wheel15 relative to the extent of rotation of the actuator 14 may becontrolled by altering the circumferential length of the inner and outertracks 27,28. If the tracks are made longer, the flexible flange portion20 will be deflected for a greater proportion of the angle through whichthe actuator 14 is rotated and so the indexing wheel drive dog 26 willbe engaged with the indexing wheel 15 to rotate the indexing wheel 15throughout that angle. If required, the tracks 27,28 could be madesufficiently long so that the indexing wheel 15 rotates during rotationof the actuator 14 through its entire angle of movement in onedirection. Alternatively, the tracks 27,28 could be made shorter toreduce the angle through which the actuator 14 and indexing wheel 15rotate together. Ideally, the track length can be selected so that theindexing wheel 15 is rotated through a sufficient angle to move thenext, unused blister, into alignment with the blister piercing element,any further rotation of the actuator 14 can either be lost motion, i.e.it performs no function or some other function. For example, if it isthe cap that is rotated, this last period of rotation of the cap canoperate a separate actuator to cause it to pierce the lid of saidblister that has just been moved into alignment with the blisterpiercing element.

It will be appreciated that the indexing mechanism 11 is designed toenable a stroke to be aborted when the actuator 14 or cap has beenrotated through an angle which is sufficient to cause initial indexingof the strip but which is not such that the drive to the indexing wheel15 has disengaged, i.e. a position in which the flange drive dog 22 hasnot reached the end of the innermost track 27. If the stroke is abortedand the actuator 14 returned to its rest position before drive to theindexing wheel 15 has disengaged, the strip will be driven backwardsinto its original position as a rear surface 26 b of the indexing wheeldrive dog 26 will engage a preceding vane 15 b to drive the indexingwheel 15 in the opposite direction. It will be appreciated that this hasthe advantage that the user may partially open the actuator 14 to enablethem to inspect and/or clean a mouthpiece and then close it againwithout having indexed the strip or pierced a blister.

The flange 19 is provided with a downwardly depending lug 19 a (see FIG.8 b) that engages with a feature (not shown) on the casework when theactuator or cap has reached its fully open extent, thereby preventingany further rotation of the actuator or cap.

A variety of medicaments may be administered alone by using inhalers ofthe invention. Specific active agents or drugs that may be used include,but are not limited to, agents of one or more of the following classeslisted below.

1) Adrenergic agonists such as, for example, amphetamine, apraclonidine,bitolterol, clonidine, colterol, dobutamine, dopamine, ephedrine,epinephrine, ethylnorepinephrine, fenoterol, formoterol, guanabenz,guanfacine, hydroxyamphetamine, isoetharine, isoproterenol, isotharine,mephenterine, metaraminol, methamphetamine, methoxamine, methpentermine,methyldopa, methylphenidate, metaproterenol, metaraminol, mitodrine,naphazoline, norepinephrine, oxymetazoline, pemoline, phenylephrine,phenylethylamine, phenylpropanolamine, pirbuterol, prenalterol,procaterol, propylhexedrine, pseudoephedrine, ritodrine, salbutamol,salmeterol, terbutaline, tetrahydrozoline, tramazoline, tyramine andxylometazoline.

2) Adrenergic antagonists such as, for example, acebutolol, alfuzosin,atenolol, betaxolol, bisoprolol, bopindolol, bucindolol, bunazosin,butyrophenones, carteolol, carvedilol, celiprolol, chlorpromazine,doxazosin, ergot alkaloids, esmolol, haloperidol, indoramin, ketanserin,labetalol, levobunolol, medroxalol, metipranolol, metoprolol, nebivolol,nadolol, naftopidil, oxprenolol, penbutolol, phenothiazines,phenoxybenzamine, phentolamine, pindolol, prazosin, propafenone,propranolol, sotalol, tamsulosin, terazosin, timolol, tolazoline,trimazosin, urapidil and yohimbine.

3) Adrenergic neurone blockers such as, for example, bethanidine,debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine, guanoclorand guanoxan.

4) Drugs for treatment of addiction, such as, for example,buprenorphine.

5) Drugs for treatment of alcoholism, such as, for example, disulfuram,naloxone and naltrexone.

6) Drugs for Alzheimer's disease management, includingacetylcholinesterase inhibitors such as, for example, donepezil,galantamine, rivastigmine and tacrin.

7) Anaesthetics such as, for example amethocaine, benzocaine,bupivacaine, hydrocortisone, ketamine, lignocaine, methylprednisolone,prilocaine, proxymetacaine, ropivacaine and tyrothricin.

8) Angiotensin converting enzyme inhibitors such as, for example,captopril, cilazapril, enalapril, fosinopril, imidapril hydrochloride,lisinopril, moexipril hydrochloride, perindopril, quinapril, ramipriland trandolapril.

9) Angiotensin II receptor blockers, such as, for example, candesartan,cilexetil, eprosartan, irbesartan, losartan, medoxomil, olmesartan,telmisartan and valsartan.

10) Antiarrhythmics such as, for example, adenosine, amidodarone,disopyramide, flecainide acetate, lidocaine hydrochloride, mexiletine,procainamide, propafenone and quinidine.

11) Antibiotic and antibacterial agents (including the beta-lactams,fluoroquinolones, ketolides, macrolides, sulphonamides andtetracyclines) such as, for example, aclarubicin, amoxicillin,amphotericin, azithromycin, aztreonam chlorhexidine, clarithromycin,clindamycin, colistimethate, dactinomycin, dirithromycin, doripenem,erythromycin, fusafungine, gentamycin, metronidazole, mupirocin,natamycin, neomycin, nystatin, oleandomycin, pentamidine, pimaricin,probenecid, roxithromycin, sulphadiazine and triclosan.

12) Anti-clotting agents such as, for example, abciximab, acenocoumarol,alteplase, aspirin, bemiparin, bivalirudin, certoparin, clopidogrel,dalteparin, danaparoid, dipyridamole, enoxaparin, epoprostenol,eptifibatide, fondaparin, heparin (including low molecular weightheparin), heparin calcium, lepirudin, phenindione, reteplase,streptokinase, tenecteplase, tinzaparin, tirofiban and warfarin.

13) Anticonvulsants such as, for example, GABA analogs includingtiagabine and vigabatrin; barbiturates including pentobarbital;benzodiazepines including alprazolam, chlordiazepoxide, clobazam,clonazepam, diazepam, flurazepam, lorazepam, midazolam, oxazepam andzolazepam; hydantoins including phenyloin; phenyltriazines includinglamotrigine; and miscellaneous anticonvulsants including acetazolamide,carbamazepine, ethosuximide, fosphenyloin, gabapentin, levetiracetam,oxcarbazepine, piracetam, pregabalin, primidone, sodium valproate,topiramate, valproic acid and zonisamide.

14) Antidepressants such as, for example, tricyclic and tetracyclicantidepressants including amineptine, amitriptyline (tricyclic andtetracyclic amitryptiline), amoxapine, butriptyline, cianopramine,clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine,dosulepin, dothiepin, doxepin, imipramine, iprindole, levoprotiline,lofepramine, maprotiline, melitracen, metapramine, mianserin,mirtazapine, nortryptiline, opipramol, propizepine, protriptyline,quinupramine, setiptiline, tianeptine and trimipramine; selectiveserotonin and noradrenaline reuptake inhibitors (SNRIs) includingclovoxamine, duloxetine, milnacipran and venlafaxine; selectiveserotonin reuptake inhibitors (SSRIs) including citalopram,escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine,milnacipran, nomifensine, oxaprotiline, paroxetine, sertraline,sibutramine, venlafaxine, viqualine and zimeldine; selectivenoradrenaline reuptake inhibitors (NARIs) including demexiptiline,desipramine, oxaprotiline and reboxetine; noradrenaline and selectiveserotonin reuptake inhibitors (NASSAs) including mirtazapine; monoamineoxidase inhibitors (MAOIs) including amiflamine, brofaromine,clorgyline, α-ethyltryptamine, etoperidone, iproclozide, iproniazid,isocarboxazid, mebanazine, medifoxamine, moclobemide, nialamide,pargyline, phenelzine, pheniprazine, pirlindole, procarbazine,rasagiline, safrazine, selegiline, toloxatone and tranylcypromine;muscarinic antagonists including benactyzine and dibenzepin; azaspironesincluding buspirone, gepirone, ipsapirone, tandospirone and tiaspirone;and other antidepressants including acetaphenazine, ademetionine,S-adenosylmethionine, adrafinil, amesergide, amineptine, amperozide,benactyzine, benmoxine, binedaline, bupropion, carbamazepine,caroxazone, cericlamine, cotinine, fezolamine, flupentixol, idazoxan,kitanserin, levoprotiline, lithium salts, maprotiline, medifoxamine,methylphenidate, metralindole, minaprine, nefazodone, nisoxetine,nomifensine, oxaflozane, oxitriptan, phenyhydrazine, rolipram,roxindole, sibutramine, teniloxazine, tianeptine, tofenacin, trazadone,tryptophan, viloxazine and zalospirone.

15) Anticholinergic agents such as, for example, atropine, benzatropine,biperiden, cyclopentolate, glycopyrrolate, hyoscine, ipratropiumbromide, orphenadine hydrochloride, oxitroprium bromide, oxybutinin,pirenzepine, procyclidine, propantheline, propiverine, telenzepine,tiotropium, trihexyphenidyl, tropicamide and trospium.

16) Antidiabetic agents such as, for example, pioglitazone,rosiglitazone and troglitazone.

17) Antidotes such as, for example, deferoxamine, edrophonium chloride,fiumazenil, nalmefene, naloxone, and naltrexone.

18) Anti-emetics such as, for example, alizapride, azasetron,benzquinamide, bestahistine, bromopride, buclizine, chlorpromazine,cinnarizine, clebopride, cyclizine, dimenhydrinate, diphenhydramine,diphenidol, domperidone, dolasetron, dronabinol, droperidol,granisetron, hyoscine, lorazepam, metoclopramide, metopimazine,nabilone, ondansetron, palonosetron, perphenazine, prochlorperazine,promethazine, scopolamine, triethylperazine, trifluoperazine,triflupromazine, trimethobenzamide and tropisetron.

19) Antihistamines such as, for example, acrivastine, astemizole,azatadine, azelastine, brompheniramine, carbinoxamine, cetirizine,chlorpheniramine, cinnarizine, clemastine, cyclizine, cyproheptadine,desloratadine, dexmedetomidine, diphenhydramine, doxylamine,fexofenadine, hydroxyzine, ketotifen, levocabastine, loratadine,mizolastine, promethazine, pyrilamine, terfenadine and trimeprazine.

20) Anti-infective agents such as, for example, antivirals (includingnucleoside and non-nucleoside reverse transcriptase inhibitors andprotease inhibitors) including aciclovir, adefovir, amantadine,cidofovir, efavirenz, famiciclovir, foscarnet, ganciclovir, idoxuridine,indinavir, inosine pranobex, lamivudine, nelfinavir, nevirapine,oseltamivir, palivizumab, penciclovir, pleconaril, ribavirin,rimantadine, ritonavir, ruprintrivir, saquinavir, stavudine,valaciclovir, zalcitabine, zanamivir, zidovudine and interferons; AIDSadjunct agents including dapsone; aminoglycosides including tobramycin;antifungals including amphotericin, caspofungin, clotrimazole, econazolenitrate, fluconazole, itraconazole, ketoconazole, miconazole, nystatin,terbinafine and voriconazole; anti-malarial agents including quinine;antituberculosis agents including capreomycin, ciprofloxacin,ethambutol, meropenem, piperacillin, rifampicin and vancomycin;beta-lactams including cefazolin, cefmetazole, cefoperazone, cefoxitin,cephacetrile, cephalexin, cephaloglycin and cephaloridine;cephalosporins, including cephalosporin C and cephalothin; cephamycinssuch as cephamycin A, cephamycin B, cephamycin C, cephapirin andcephradine; leprostatics such as clofazimine; penicillins includingamoxicillin, ampicillin, amylpenicillin, azidocillin, benzylpenicillin,carbenicillin, carfecillin, carindacillin, clometocillin, cloxacillin,cyclacillin, dicloxacillin, diphenicillin, heptylpenicillin, hetacillin,metampicillin, methicillin, nafcillin, 2-pentenylpenicillin, penicillinN, penicillin O, penicillin S and penicillin V; quinolones includingciprofloxacin, clinafloxacin, difloxacin, grepafloxacin, norfloxacin,ofloxacine and temafloxacin; tetracyclines including doxycycline andoxytetracycline; miscellaneous anti-infectives including linezolide,trimethoprim and sulfamethoxazole.

21) Anti-neoplastic agents such as, for example, droloxifene, tamoxifenand toremifene.

22) Antiparkisonian drugs such as, for example, amantadine,andropinirole, apomorphine, baclofen, benserazide, biperiden,benztropine, bromocriptine, budipine, cabergoline, carbidopa, eliprodil,entacapone, eptastigmine, ergoline, galanthamine, lazabemide, levodopa,lisuride, mazindol, memantine, mofegiline, orphenadrine,trihexyphenidyl, pergolide, piribedil, pramipexole, procyclidine,propentofylline, rasagiline, remacemide, ropinerole, selegiline,spheramine, terguride and tolcapone.

23) Antipsychotics such as, for example, acetophenazine, alizapride,amisulpride, amoxapine, amperozide, aripiprazole, benperidol,benzquinamide, bromperidol, buramate, butaclamol, butaperazine,carphenazine, carpipramine, chlorpromazine, chlorprothixene,clocapramine, clomacran, clopenthixol, clospirazine, clothiapine,clozapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, loxapine, melperone, mesoridazine,metofenazate, molindrone, olanzapine, penfluridol, pericyazine,perphenazine, pimozide, pipamerone, piperacetazine, pipotiazine,prochlorperazine, promazine, quetiapine, remoxipride, risperidone,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepineand zuclopenthixol; phenothiazines including aliphatic compounds,piperidines and piperazines; thioxanthenes, butyrophenones andsubstituted benzamides.

24) Antirheumatic agents such as, for example, diclofenac, heparinoid,hydroxychloroquine and methotrexate, leflunomide and teriflunomide.

25) Anxiolytics such as, for example, adinazolam, alpidem, alprazolam,alseroxlon, amphenidone, azacyclonol, bromazepam, bromisovalum,buspirone, captodiamine, capuride, carbcloral, carbromal, chloralbetaine, chlordiazepoxide, clobenzepam, enciprazine, flesinoxan,flurazepam, hydroxyzine, ipsapiraone, lesopitron, loprazolam, lorazepam,loxapine, mecloqualone, medetomidine, methaqualone, methprylon,metomidate, midazolam, oxazepam, propanolol, tandospirone, trazadone,zolpidem and zopiclone.

26) Appetite stimulants such as, for example, dronabinol.

27) Appetite suppressants such as, for example, fenfluramine,phentermine and sibutramine; and anti-obesity treatments such as, forexample, pancreatic lipase inhibitors, serotonin and norepinephrinere-uptake inhibitors, and anti-anorectic agents.

28) Benzodiazepines such as, for example, alprazolam, bromazepam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flunitrazepam, flurazepam, halazepam,ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam,nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam andtriazolam.

29) Bisphosphonates such as, for example, alendronate sodium, sodiumclodronate, etidronate disodium, ibandronic acid, pamidronate disodium,isedronate sodium, tiludronic acid and zoledronic acid.

30) Blood modifiers such as, for example, cilostazol and dipyridamol,and blood factors.

31) Cardiovascular agents such as, for example, acebutalol, adenosine,amiloride, amiodarone, atenolol, benazepril, bisoprolol, bumetanide,candesartan, captopril, clonidine, diltiazem, disopyramide, dofetilide,doxazosin, enalapril, esmolol, ethacrynic acid, flecanide, furosemide,gemfibrozil, ibutilide, irbesartan, labetolol, losartan, lovastatin,metolazone, metoprolol, mexiletine, nadolol, nifedipine, pindolol,prazosin, procainamide, propafenone, propranolol, quinapril, quinidine,ramipril, sotalol, spironolactone, telmisartan, tocamide, torsemide,triamterene, valsartan and verapamil.

32) Calcium channel blockers such as, for example, amlodipine, bepridil,diltiazem, felodipine, flunarizine, gallopamil, isradipine, lacidipine,lercanidipine, nicardipine, nifedipine, nimodipine and verapamil.

33) Central nervous system stimulants such as, for example, amphetamine,brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine,fenfluramine, mazindol, methyphenidate, modafmil, pemoline, phentermineand sibutramine.

34) Cholesterol-lowering drugs such as, for example, acipimox,atorvastatin, ciprofibrate, colestipol, colestyramine, bezafibrate,ezetimibe, fenofibrate, fluvastatin, gemfibrozil, ispaghula, nictotinicacid, omega-3 triglycerides, pravastatin, rosuvastatin and simvastatin.

35) Drugs for cystic fibrosis management such as, for example,Pseudomonas aeruginosa infection vaccines (eg Aerugen™), alpha1-antitripsin, amikacin, cefadroxil, denufosol, duramycin, glutathione,mannitol, and tobramycin.

36) Diagnostic agents such as, for example, adenosine and aminohippuricacid.

37) Dietary supplements such as, for example, melatonin and vitaminsincluding vitamin E.

38) Diuretics such as, for example, amiloride, bendroflumethiazide,bumetanide, chlortalidone, cyclopenthiazide, furosemide, indapamide,metolazone, spironolactone and torasemide.

39) Dopamine agonists such as, for example, amantadine, apomorphine,bromocriptine, cabergoline, lisuride, pergolide, pramipexole andropinerole.

40) Drugs for treating erectile dysfunction, such as, for example,apomorphine, apomorphine diacetate, moxisylyte, phentolamine,phosphodiesterase type 5 inhibitors, such as sildenafil, tadalafil,vardenafil and yohimbine.

41) Gastrointestinal agents such as, for example, atropine, hyoscyamine,famotidine, lansoprazole, loperamide, omeprazole and rebeprazole.

42) Hormones and analogues such as, for example, cortisone, epinephrine,estradiol, insulin, Ostabolin-C, parathyroid hormone and testosterone.

43) Hormonal drugs such as, for example, desmopressin, lanreotide,leuprolide, octreotide, pegvisomant, protirelin, salcotonin, somatropin,tetracosactide, thyroxine and vasopressin.

44) Hypoglycaemics such as, for example, sulphonylureas includingglibenclamide, gliclazide, glimepiride, glipizide and gliquidone;biguanides including metformin; thiazolidinediones includingpioglitazone, rosiglitazone, nateglinide, repaglinide and acarbose.

45) Immunoglobulins.

46) Immunomodulators such as, for example, interferon (e.g. interferonbeta-1a and interferon beta-1b) and glatiramer.

47) Immunosupressives such as, for example, azathioprine, cyclosporin,mycophenolic acid, rapamycin, sirolimus and tacrolimus.

48) Mast cell stabilizers such as, for example, cromoglycate,iodoxamide, nedocromil, ketotifen, tryptase inhibitors and pemirolast.

49) Drugs for treatment of migraine headaches such as, for example,almotriptan, alperopride, amitriptyline, amoxapine, atenolol, clonidine,codeine, coproxamol, cyproheptadine, dextropropoxypene,dihydroergotamine, diltiazem, doxepin, ergotamine, eletriptan,fluoxetine, frovatriptan, isometheptene, lidocaine, lisinopril,lisuride, loxapine, methysergide, metoclopramide, metoprolol, nadolol,naratriptan, nortriptyline, oxycodone, paroxetine, pizotifen,pizotyline, prochlorperazine propanolol, propoxyphene, protriptyline,rizatriptan, sertraline, sumatriptan, timolol, tolfenamic acid,tramadol, verapamil, zolmitriptan, and non-steroidal anti-inflammatorydrugs.

50) Drugs for treatment of motion sickness such as, for example,diphenhydramine, promethazine and scopolamine.

51) Mucolytic agents such as N-acetylcysteine, ambroxol, amiloride,dextrans, heparin, desulphated heparin, low molecular weight heparin andrecombinant human DNase.

52) Drugs for multiple sclerosis management such as, for example,bencyclane, methylprednisolone, mitoxantrone and prednisolone.

53) Muscle relaxants such as, for example, baclofen, chlorzoxazone,cyclobenzaprine, methocarbamol, orphenadrine, quinine and tizanidine.

54) NMDA receptor antagonists such as, for example, mementine.

55) Nonsteroidal anti-inflammatory agents such as, for example,aceclofenac, acetaminophen, alminoprofen, amfenac, aminopropylon,amixetrine, aspirin, benoxaprofen, bromfenac, bufexamac, carprofen,celecoxib, choline, cinchophen, cinmetacin, clometacin, clopriac,diclofenac, diclofenac sodium, diflunisal, ethenzamide, etodolac,etoricoxib, fenoprofen, flurbiprofen, ibuprofen, indomethacin,indoprofen, ketoprofen, ketorolac, loxoprofen, mazipredone,meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, parecoxib, phenylbutazone, piroxicam, pirprofen, rofecoxib,salicylate, sulindac, tiaprofenic acid, tolfenamate, tolmetin andvaldecoxib.

56) Nucleic-acid medicines such as, for example, oligonucleotides, decoynucleotides, antisense nucleotides and other gene-based medicinemolecules.

57) Opiates and opioids such as, for example, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,butorphanol, carbiphene, cipramadol, clonitazene, codeine, codeinephosphate, dextromoramide, dextropropoxyphene, diamorphine,dihydrocodeine, dihydromorphine, diphenoxylate, dipipanone, fentanyl,hydromorphone, L-alpha acetyl methadol, levorphanol, lofentanil,loperamide, meperidine, meptazinol, methadone, metopon, morphine,nalbuphine, nalorphine, oxycodone, papavereturn, pentazocine, pethidine,phenazocine, pholcodeine, remifentanil, sufentanil, tramadol, andcombinations thereof with an anti-emetic.

58) Opthalmic preparations such as, for example, betaxolol andketotifen.

59) Osteoporosis preparations such as, for example, alendronate,estradiol, estropitate, raloxifene and risedronate.

60) Other analgesics such as, for example, apazone, benzpiperylon,benzydamine, caffeine, cannabinoids, clonixin, ethoheptazine,flupirtine, nefopam, orphenadrine, pentazocine, propacetamol andpropoxyphene.

61) Other anti-inflammatory agents such as, for example, B-cellinhibitors, p38 MAP kinase inhibitors and TNF inhibitors.

62) Phosphodiesterase inhibitors such as, for example, non-specificphosphodiesterase inhibitors including theophylline, theobromine, IBMX,pentoxifylline and papaverine; phosphodiesterase type 3 inhibitorsincluding bipyridines such as milrinone, aminone and olprinone;imidazolones such as piroximone and enoximone; imidazolines such asimazodan and 5-methyl-imazodan; imidazo-quinoxalines; anddihydropyridazinones such as indolidan and LY181512(5-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-1,3-dihydro-indol-2-one);dihydroquinolinone compounds such as cilostamide, cilostazol, andvesnarinone; motapizone; phosphodiesterase type 4 inhibitors such ascilomilast, etazolate, rolipram, oglemilast, roflumilast, ONO 6126,tolafentrine and zardaverine, and including quinazolinediones such asnitraquazone and nitraquazone analogs; xanthine derivatives such asdenbufylline and arofylline; tetrahydropyrimidones such as atizoram; andoxime carbamates such as filaminast; and phosphodiesterase type 5inhibitors including sildenafil, zaprinast, vardenafil, tadalafil,dipyridamole, and the compounds described in WO 01/19802, particularly(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine,and(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]-pyrimidine).

63) Potassium channel modulators such as, for example, cromakalim,diazoxide, glibenclamide, levcromakalim, minoxidil, nicorandil andpinacidil.

64) Prostaglandins such as, for example, alprostadil, dinoprostone,epoprostanol and misoprostol.

65) Respiratory agents and agents for the treatment of respiratorydiseases including bronchodilators such as, for example, the β₂-agonistsbambuterol, bitolterol, broxaterol, carmoterol, clenbuterol, fenoterol,formoterol, indacaterol, levalbuterol, metaproterenol, orciprenaline,picumeterol, pirbuterol, procaterol, reproterol, rimiterol, salbutamol,salmeterol, terbutaline and the like; inducible nitric oxide synthase(iNOS) inhibitors; the antimuscarinics ipratropium, ipratropium bromide,oxitropium, tiotropium, glycopyrrolate and the like; the xanthinesaminophylline, theophylline and the like; adenosine receptorantagonists, cytokines such as, for example, interleukins andinterferons; cytokine antagonists and chemokine antagonists includingcytokine synthesis inhibitors, endothelin receptor antagonists, elastaseinhibitors, integrin inhibitors, leukotrine receptor antagonists,prostacyclin analogues, and ablukast, ephedrine, epinephrine, fenleuton,iloprost, iralukast, isoetharine, isoproterenol, montelukast,ontazolast, pranlukast, pseudoephedrine, sibenadet, tepoxalin,verlukast, zafirlukast and zileuton.

66) Sedatives and hypnotics such as, for example, alprazolam,butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam,flurazepam, lorazepam, midazolam, temazepam, triazolam, zaleplon,zolpidem, and zopiclone.

67) Serotonin agonists such as, for example,1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, buspirone,m-chlorophenylpiperazine, cisapride, ergot alkaloids, gepirone,8-hydroxy-(2-N,N-dipropylamino)-tetraline, ipsaperone, lysergic aciddiethylamide, 2-methyl serotonin, mezacopride, sumatriptan, tiaspirone,trazodone and zacopride.

68) Serotonin antagonists such as, for example, amitryptiline,azatadine, chlorpromazine, clozapine, cyproheptadine, dexfenfluramine,R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol,dolasetron, fenclonine, fenfluramine, granisetron, ketanserin,methysergide, metoclopramide, mianserin, ondansetron, risperidone,ritanserin, trimethobenzamide and tropisetron.

69) Steroid drugs such as, for example, alcometasone, beclomethasone,beclomethasone dipropionate, betamethasone, budesonide, butixocort,ciclesonide, clobetasol, deflazacort, diflucortolone, desoxymethasone,dexamethasone, fludrocortisone, flunisolide, fluocinolone,fluometholone, fluticasone, fluticasone proprionate, hydrocortisone,methylprednisolone, mometasone, nandrolone decanoate, neomycin sulphate,prednisolone, rimexolone, rofleponide, triamcinolone and triamcinoloneacetonide.

70) Sympathomimetic drugs such as, for example, adrenaline,dexamfetamine, dipirefin, dobutamine, dopamine, dopexamine,isoprenaline, noradrenaline, phenylephrine, pseudoephedrine, tramazolineand xylometazoline.

71) Nitrates such as, for example, glyceryl trinitrate, isosorbidedinitrate and isosorbide mononitrate.

72) Skin and mucous membrane agents such as, for example, bergapten,isotretinoin and methoxsalen.

73) Smoking cessation aids such as, for example, bupropion, nicotine andvarenicline.

74) Drugs for treatment of Tourette's syndrome such as, for example,pimozide.

75) Drugs for treatment of urinary tract infections such as, forexample, darifenicin, oxybutynin, propantheline bromide and tolteridine.

76) Vaccines.

77) Drugs for treating vertigo such as, for example, betahistine andmeclizine.

78) Therapeutic proteins and peptides such as acylated insulin,glucagon, glucagon-like peptides, exendins, insulin, insulin analogues,insulin aspart, insulin detemir, insulin glargine, insulin glulisine,insulin lispro, insulin zinc, isophane insulins, neutral, regular andinsoluble insulins, and protamine zinc insulin.

79) Anticancer agents such as, for example, anthracyclines, doxorubicin,idarubicin, epirubicin, methotrexate, taxanes, paclitaxel, docetaxel,cisplatin, vinca alkaloids, vincristine and 5-fluorouracil.

80) Pharmaceutically acceptable salts or derivatives of any of theforegoing.

It should be noted that drugs listed above under a particular indicationor class may also find utility in other indications. A plurality ofactive agents can be employed in the practice of the present invention.An inhaler according to the invention may also be used to delivercombinations of two or more different active agents or drugs. Specificcombinations of two medicaments which may be mentioned includecombinations of steroids and β₂-agonists. Examples of such combinationsare beclomethasone and formoterol; beclomethasone and salmeterol;fluticasone and formoterol; fluticasone and salmeterol; budesonide andformoterol; budesonide and salmeterol; flunisolide and formoterol;flunisolide and salmeterol; ciclesonide and formoterol; ciclesonide andsalmeterol; mometasone and formoterol; and mometasone and salmeterol.Specifically, inhalers according to the invention may also be used todeliver combinations of three different active agents or drugs.

It will be clear to a person of skill in the art that, whereappropriate, the active agents or drugs may be linked to a carriermolecule or molecules and/or used in the form of prodrugs, salts, asesters, or as solvates to optimise the activity and/or stability of theactive agent or drug.

Anticholinergic agents are referred to above (see No. 15). It is alsoenvisaged that the pharmaceutical composition may comprise one or more,preferably one, anticholinergic 1, optionally in combination with apharmaceutically acceptable excipient.

The anticholinergic 1 can be selected from the group consisting of

a) tiotropium salts 1a,b) compounds of formula 1c

whereinA denotes a double-bonded group selected from among

X⁻ denotes an anion with a single negative charge, preferably an anionselected from the group consisting of fluoride, chloride, bromide,iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate andp-toluenesulphonate,R¹ and R² which may be identical or different denote a group selectedfrom among methyl, ethyl, n-propyl and iso-propyl, which may optionallybe substituted by hydroxy or fluorine, preferably unsubstituted methyl;R³, R⁴, R⁵ and R⁶, which may be identical or different, denote hydrogen,methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine,bromine, CN, CF₃ or NO₂;R⁷ denotes hydrogen, methyl, ethyl, methyloxy, ethyloxy, —CH₂—F,—CH₂—CH₂—F, -0-CH₂—F, -0-CH₂—CH₂—F, —CH₂—OH, —CH₂—CH₂—OH, CF₃, —CH₂—OMe,—CH₂—CH₂—OMe, —CH₂—OEt, —CH₂—CH₂—OEt, —O—COMe, —O—COEt, -Q-COCF₃,-Q-COCF₃, fluorine, chlorine or bromine;c) compounds of formula 1d

whereinA, X⁻, R¹ and R² may have the meanings as mentioned hereinbefore andwherein R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹², which may be identical ordifferent, denote hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy,fluorine, chlorine, bromine, CN, CF₃ or NO₂, with the proviso that atleast one of the groups R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² is not hydrogen,d) compounds of formula 1e

wherein A and X⁻ may have the meanings as mentioned hereinbefore, andwhereinR¹⁵ denotes hydrogen, hydroxy, methyl, ethyl, —CF₃, CHF₂ or fluorine;R^(1′) and R^(2′) which may be identical or different denote C₁-C₅-alkylwhich may optionally be substituted by C₃-C₆-cycloalkyl, hydroxy orhalogen, orR^(1′) and R2′ together denote a —C₃-C₅-alkylene-bridge;R¹³, R¹⁴, R^(13′) and R^(14′) which may be identical or different denotehydrogen, —C₁-C₄-alkyl, —C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, CN, NO₂or halogen,e) compounds of formula 1f

wherein X⁻ may have the meanings as mentioned hereinbefore, and whereinD and B which may be identical or different, preferably identical,denote —O, —S, —NH, —CH₂, —CH═CH, or —N(C₁-C₄-alkyl)-;R¹⁶ denotes hydrogen, hydroxy, —C₁-C₄-alkyl, —C₁-C₄-alkyloxy,—C₁-C₄-alkylene-Halogen, —O—C₁-C₄ alkylene-halogen, —C₁-C₄-alkylene-OH,—CF₃, CHF₂, —C₁-C₄-alkylene-C₁-C₄ alkyloxy, —O—COC₁-C₄-alkyl,—O—COC₁-C₄-alkylene-halogen, —C₁-C₄-alkylene-C₃-C₆-cycloalkyl, —O—COCF₃or halogen;R^(1″) and R^(2″) which may be identical or different, denote—C₁-C₅-alkyl, which may optionally be substituted by —C₃-C₆-cycloalkyl,hydroxy or halogen, orR^(1″) and R^(2″) together denote a —C3-C5-alkylene bridge;R¹⁷, R¹⁸, R^(17′) and R^(18′), which may be identical or different,denote hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, CN,NO₂ or halogen;R^(x) and R^(x′) which may be identical or different, denote hydrogen,C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, CN, NO₂ or halogen orR^(x) and R^(x′) together denote a single bond or a bridging groupselected from among the bridges —O, —S, —NH, —CH₂, —CH₂—CH₂—,—N(C₁-C₄-alkyl), —CH(C₁-C₄-alkyl)- and —C(C₁-C₄-alkyl)₂, andf) compounds of formula 1g

wherein X⁻ may have the meanings as mentioned hereinbefore, and whereinA′ denotes a double-bonded group selected from among

R¹⁹ denotes hydroxy, methyl, hydroxymethyl, ethyl, —CF₃, CHF₂ orfluorine;R^(1′″) and R^(2′″) which may be identical or different denoteC₁-C₅-alkyl which may optionally be substituted by C₃-C₆-cycloalkyl,hydroxy or halogen, orR^(1′″) and R^(2′″) together denote a —C₃-C₅-alkylene-bridge;R²⁰, R²¹, R^(20′) and R^(21′) which may be identical or different denotehydrogen, —C₁-C₄-alkyl, —C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, CN, NO₂or halogen.

The compounds of formula 1c are known in the art (WO 02/32899).

In a preferred embodiment of the invention the method comprisesadministration of compounds of formula 1c, wherein

X⁻ denotes bromide;R¹ and R² which may be identical or different denote a group selectedfrom methyl and ethyl, preferably methyl;R³, R⁴, R⁵ and R⁶, which may be identical or different, denote hydrogen,methyl, methyloxy, chlorine or fluorine;R⁷ denotes hydrogen, methyl or fluorine, optionally together with apharmaceutically acceptable excipient.

Of particular importance are compounds of general formula 1c, wherein Adenotes a double-bonded group selected from among

The compounds of formula 1c, may optionally be administered in the formof the individual optical isomers, mixtures of the individualenantiomers or racemates thereof.

Of particular importance within a method according to the invention arethe following compounds of formula 1c:

-   tropenol 2,2-diphenylpropionic acid ester methobromide,-   scopine 2,2-diphenylpropionic acid ester methobromide,-   scopine 2-fluoro-2,2-diphenylacetic acid ester methobromide and-   tropenol 2-fluoro-2,2-diphenylacetic acid ester methobromide.

The compounds of formula 1d are known in the art (WO 02/32898).

In a preferred embodiment of the invention the method comprisesadministration of compounds of formula 1d, wherein

A denotes a double-bonded group selected from among

X⁻ denotes bromide;R¹ and R² which may be identical or different denote methyl or ethyl,preferably methyl;R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹², which may be identical or different,denote hydrogen, fluorine, chlorine or bromine, preferably fluorine withthe proviso that at least one of the groups R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹²not hydrogen, optionally together with a pharmaceutically acceptableexcipient.

Of particular importance within the method according to the inventionare the following compounds of formula 1d:

-   tropenol 3,3′,4,4′-tetrafluorobenzilic acid ester methobromide,-   scopine 3,3′,4,4′-tetrafluorobenzilic acid ester methobromide,-   scopine 4,4′-difluorobenzilic acid ester methobromide,-   tropenol 4,4′-difluorobenzilic acid ester methobromide,-   scopine 3,3′-difluorobenzilic acid ester methobromide, and-   tropenol 3,3′-difluorobenzilic acid ester methobromide.

The pharmaceutical compositions according to the invention may containthe compounds of formula 1d optionally in the form of the individualoptical isomers, mixtures of the individual enantiomers or racematesthereof.

The compounds of formula 1e are known in the art (WO 03/064419).

In a preferred embodiment of the invention the method comprisesadministration of compounds of formula 1e, wherein

A denotes a double-bonded group selected from among

X⁻ denotes an anion selected from among chloride, bromide andmethanesulphonate, preferably bromide;R¹⁵ denotes hydroxy, methyl or fluorine, preferably methyl or hydroxy;R^(1′) and R^(2′) which may be identical or different represent methylor ethyl, preferably methyl;R¹³, R¹⁴, R^(13′) and R^(14′) which may be identical or differentrepresent hydrogen, —CF₃, —CHF₂ or fluorine, preferably hydrogen orfluorine, optionally together with a pharmaceutically acceptableexcipient.

In another preferred embodiment of the invention the method comprisesadministration of compounds of formula 1e, wherein

A denotes a double-bonded group selected from among

X⁻ denotes bromide;R¹⁵ denotes hydroxy or methyl, preferably methyl;R^(1′) and R^(2′) which may be identical or different represent methylor ethyl, preferably methyl;R¹³, R¹⁴, R^(13′) and R^(14′) which may be identical or differentrepresent hydrogen or fluorine, optionally together with apharmaceutically acceptable excipient.

Of particular importance within the method according to the inventionare the following compounds of formula 1e:

-   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;-   tropenol 9-fluoro-fluorene-9-carboxylate methobromide;-   scopine 9-hydroxy-fluorene-9-carboxylate methobromide;-   scopine 9-fluoro-fluorene-9-carboxylate methobromide;-   tropenol 9-methyl-fluorene-9-carboxylate methobromide;-   scopine 9-methyl-fluorene-9-carboxylate methobromide.

The pharmaceutical compositions according to the invention may containthe compounds of formula 1e optionally in the form of the individualoptical isomers, mixtures of the individual enantiomers or racematesthereof.

The compounds of formula 1f are known in the art (WO 03/064418).

In another preferred embodiment of the invention the method comprisesadministration of compounds of formula 1f wherein

X⁻ denotes chloride, bromide, or methanesulphonate, preferably bromide;D and B which may be identical or different, preferably identical,denote —O, —S, —NH or —CH═CH—;R¹⁶ denotes hydrogen, hydroxy, —C₁-C₄-alkyl, —C₁-C₄alkyloxy, —CF₃,—CHF₂, fluorine, chlorine or bromine;R^(1″) and R^(2″) which may be identical or different, denoteC₁-C₄-alky, which may optionally be substituted by hydroxy, fluorine,chlorine or bromine, orR^(1″) and R^(2″) together denote a —C₃-C₄-alkylene-bridge;R¹⁷, R¹⁸, R^(17′) and R^(18′), which may be identical or different,denote hydrogen, C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, CN,NO₂, fluorine, chlorine or bromine;R^(x) and R^(x′) which may be identical or different, denote hydrogen,C₁-C₄-alkyl, C₁-C₄-alkyloxy, hydroxy, —CF₃, —CHF₂, CN, NO₂, fluorine,chlorine or bromine orR^(x) and R^(x′) together denote a single bond or a bridging groupselected from among the bridges —O, —S, —NH— and —CH₂—, optionallytogether with a pharmaceutically acceptable excipient.

In another preferred embodiment of the invention the method comprisesadministration of compounds of formula 1f, wherein

X⁻ denotes chloride, bromide, or methanesulphonate, preferably bromide;D and B which may be identical or different, preferably identical,denote —S or —CH═CH—;R¹⁶ denotes hydrogen, hydroxy or methyl;R^(1″) and R^(2″) which may be identical or different, denote methyl orethyl;R¹⁷, R¹⁸, R^(17′) and R^(18′), which may be identical or different,denote hydrogen, —CF₃ or fluorine, preferably hydrogen;R^(x) and R^(x′) which may be identical or different, denote hydrogen,—CF₃ or fluorine, preferably hydrogen orR^(x) and R^(x′) together denote a single bond or the bridging group—O—, optionally together with a pharmaceutically acceptable excipient.

In another preferred embodiment of the invention the method comprisesadministration of compounds of formula 1f wherein denotes bromide;

X⁻ denotes bromide;D and B denote —CH═CH—;R¹⁶ denotes hydrogen, hydroxy or methyl;R^(1″) and R^(2″) denote methyl;R¹⁷, R¹⁸, R^(17′) and R^(18′), which may be identical or different,denote hydrogen or fluorine, preferably hydrogen;R^(x) and R^(x′) which may be identical or different, denote hydrogen orfluorine, preferably hydrogen orR^(x) and R^(x′) together denote a single bond or the bridging group—O—, optionally together with a pharmaceutically acceptable excipient.

Of particular importance within the method according to the inventionare the following compounds of formula 1f:

cyclopropyltropine benzilate methobromide; cyclopropyltropine2,2-diphenylpropionate methobromide; cyclopropyltropine9-hydroxy-xanthene-9-carboxylate methobromide; cyclopropyltropine9-methyl-fluorene-9-carboxylate methobromide; cyclopropyltropine9-methyl-xanthene-9-carboxylate methobromide; cyclopropyltropine9-hydroxy-fluorene-9-carboxylate methobromide; cyclopropyltropine methyl4,4′-difluorobenzilate methobromide.

The pharmaceutical compositions according to the invention may containthe compounds of formula 1f optionally in the form of the individualoptical isomers, mixtures of the individual enantiomers or racematesthereof.

The compounds of formula 1g are known in the art (WO 03/064417).

In another preferred embodiment of the invention the method comprisesadministration of compounds of formula 1g wherein

A′ denotes a double-bonded group selected from among

X⁻ denotes chloride, bromide or methanesulphonate, preferably bromide;R¹⁹ denotes hydroxy or methyl;R^(1′″) and R^(2′″) which may be identical or different represent methylor ethyl, preferably methyl;R²⁰, R²¹, R^(20′) and R^(21′) which may be identical or differentrepresent hydrogen, —CF₃, —CHF₂ or fluorine, preferably hydrogen orfluorine, optionally together with a pharmaceutically acceptableexcipient.

In another preferred embodiment of the invention the method comprisesadministration of compounds of formula 1g wherein

A′ denotes a double-bonded group selected from among

X⁻ denotes bromide;R¹⁹ denotes hydroxy or methyl, preferably methyl;R^(1′″) and R^(2′″) which may be identical or different represent methylor ethyl, preferably methyl;R³, R⁴, R^(3′) and R^(4′) which may be identical or different representhydrogen or fluorine, optionally together with a pharmaceuticallyacceptable excipient.

Of particular importance within the method according to the inventionare the following compounds of formula 1g:

-   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxy-xanthene-9-carboxylate methobromide;-   tropenol 9-methyl-xanthene-9-carboxylate methobromide;-   scopine 9-methyl-xanthene-9-carboxylate methobromide;-   tropenol 9-ethyl-xanthene-9-carboxylate methobromide;-   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;-   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide.

The pharmaceutical compositions according to the invention may containthe compounds of formula 1g optionally in the form of the individualoptical isomers, mixtures of the individual enantiomers or racematesthereof.

The alkyl groups used, unless otherwise stated, are branched andunbranched alkyl groups having 1 to 5 carbon atoms. Examples include:methyl, ethyl, propyl or butyl. The groups methyl, ethyl, propyl orbutyl may optionally also be referred to by the abbreviations Me, Et,Prop or Bu. Unless otherwise stated, the definitions propyl and butylalso include all possible isomeric forms of the groups in question.Thus, for example, propyl includes n-propyl and iso-propyl, butylincludes iso-butyl, sec. butyl and tert.-butyl, etc.

The cycloalkyl groups used, unless otherwise stated, are alicyclicgroups with 3 to 6 carbon atoms. These are the cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl groups. According to the inventioncyclopropyl is of particular importance within the scope of the presentinvention.

The alkylene groups used, unless otherwise stated, are branched andunbranched double-bonded alkyl bridges with 1 to 5 carbon atoms.Examples include: methylene, ethylene, propylene or butylene.

The alkylene-halogen groups used, unless otherwise stated, are branchedand unbranched double-bonded alkyl bridges with 1 to 4 carbon atomswhich may be mono-, di- or trisubstituted, preferably disubstituted, bya halogen. Accordingly, unless otherwise stated, the term alkylene-OHgroups denotes branched and unbranched double-bonded alkyl bridges with1 to 4 carbon atoms which may be mono-, di- or trisubstituted,preferably monosubstituted, by a hydroxy.

The alkyloxy groups used, unless otherwise stated, are branched andunbranched alkyl groups with 1 to 5 carbon atoms which are linked via anoxygen atom. The following may be mentioned, for example: methyloxy,ethyloxy, propyloxy or butyloxy. The groups methyloxy, ethyloxy,propyloxy or butyloxy may optionally also be referred to by theabbreviations MeO, EtO, PropO or BuO. Unless otherwise stated, thedefinitions propyloxy and butyloxy also include all possible isomericforms of the groups in question. Thus, for example, propyloxy includesn-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec.butyloxy and tert.-butyloxy, etc. The word alkoxy may also possibly beused within the scope of the present invention instead of the wordalkyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy mayoptionally also be referred to as methoxy, ethoxy, propoxy or butoxy.

The alkylene-alkyloxy groups used, unless otherwise stated, are branchedand unbranched double-bonded alkyl bridges with 1 to 5 carbon atomswhich may be mono-, di- or trisubstituted, preferably monosubstituted,by an alkyloxy group.

The —O—CO-alkyl groups used, unless otherwise stated, are branched andunbranched alkyl groups with 1 to 4 carbon atoms which are bonded via anester group. The alkyl groups are bonded directly to the carbonylcarbonof the ester group. The term —O—CO-alkyl-halogen group should beunderstood analogously. The group —O—CO—CF₃ denotes trifluoroacetate.

Within the scope of the present invention halogen denotes fluorine,chlorine, bromine or iodine. Unless otherwise stated, fluorine andbromine are the preferred halogens. The group CO denotes a carbonylgroup.

The inhalation device according to the invention comprises the compoundsof formula 1 preferably in admixture with a pharmaceutically acceptableexcipient to form a powder mixture. The following pharmaceuticallyacceptable excipients may be used to prepare these inhalable powdermixtures according to the invention: monosaccharides (e.g. glucose orarabinose), disaccharides (e.g. lactose, saccharose, maltose,trehalose), oligo- and polysaccharides (e.g. dextrane), polyalcohols(e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calciumcarbonate) or mixtures of these excipients with one another. Preferably,mono- or disaccharides are used, while the use of lactose or glucose ispreferred, particularly, but not exclusively, in the form of theirhydrates. For the purposes of the invention, lactose and trehalose arethe particularly preferred excipients, while lactose, preferably in formof its monohydrate is most particularly preferred.

The compounds of formula 1 may be used in the form of their racemates,enantiomers or mixtures thereof. The separation of enantiomers from theracemates may be carried out using methods known in the art (e.g. bychromatography on chiral phases, etc.).

Optionally, the inhalation device according to the invention containsplural of doses of a medicament in powder form that contains, beside onecompound of formula 1, another active ingredient.

Preferably the additional active ingredient is a beta₂ agonists 2 whichis selected from the group consisting of albuterol, bambuterol,bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol,hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol,mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol,procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol,soterenot, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035,HOKU-81, KUL-1248,3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide,5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-0X0-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanoland1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, the enantiomers, thediastereomers and optionally the pharmacologically acceptable acidaddition salts and the hydrates thereof.

According to the instant invention more preferred beta₂ agonists 2 areselected from the group consisting of bambuterol, bitolterol,carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,pirbuterol, procaterol, reproterol, salmeterol, sulphonterol,terbutaline, tolubuterol,3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide,5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-0X0-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanoland1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, the enantiomers, thediastereomers and optionally the pharmacologically acceptable acidaddition salts and the hydrates thereof.

More preferably, the betamimetics 2 used as within the compositionsaccording to the invention are selected from among fenoterol,formoterol, salmeterol,3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide,5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of the racemates, the enantiomers, thediastereomers and optionally the pharmacologically acceptable acidaddition salts thereof, and the hydrates thereof. Of the betamimeticsmentioned above the compounds formoterol, salmeterol,3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide,and5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-oneare particularly preferred, optionally in the form of the racemates, theenantiomers, the diastereomers and optionally the pharmacologicallyacceptable acid addition salts thereof, and the hydrates thereof. Of thebetamimetics mentioned above the compounds formoterol and salmeterol areparticularly preferred, optionally in the form of the racemates, theenantiomers, the diastereomers and optionally the pharmacologicallyacceptable acid addition salts thereof, and the hydrates thereof.

Examples of pharmacologically acceptable acid addition salts of thebetamimetics 2 according to the invention are the pharmaceuticallyacceptable salts which are selected from among the salts of hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylicacid, 4-phenylcinnamic acid, 5-(2,4-difluorophenyl)salicylic acid ormaleic acid. If desired, mixtures of the abovementioned acids may alsobe used to prepare the salts 2.

According to the invention, the salts of the betamimetics 2 selectedfrom among the hydrochloride, hydrobromide, sulphate, phosphate,fumarate, methanesulphonate, 4-phenylcinnamate,5-(2,4-difluorophenyl)salicylate, maleate and xinafoate are preferred.Particularly preferred are the salts of 2 in the case of salmeterolselected from among the hydrochloride, sulphate, 4-phenylcinnamate,5-(2,4-difluorophenyl)salicylate and xinafoate, of which the4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate and especiallyxinafoate are particularly important. Particularly preferred are thesalts of 2 in the case of formoterol selected from the hydrochloride,sulphate and fumarate, of which the hydrochloride and fumarate areparticularly preferred, such as formoterol fumarate.

Salts of salmeterol, formoterol,3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulfoneamide,and5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,are preferably used as the betamimetics 2 according to the invention. Ofparticular importance are salmeterol and formoterol salts. Any referenceto the term betamimetics 2 also includes a reference to the relevantenantiomers or mixtures thereof. In the pharmaceutical compositionsaccording to the invention, the compounds 2 may be present in the formof their racemates, enantiomers or mixtures thereof. The separation ofthe enantiomers from the racemates may be carried out using methodsknown in the art (e.g. by chromatography on chiral phases, etc.) If thecompounds 2 are used in the form of their enantiomers, it isparticularly preferable to use the enantiomers in the R configuration atthe C—OH group.

Optionally, the inhalation device according to the invention containsplural of doses of a medicament in powder form that contains beside onecompound of formula 1 a steroid 3 as another active ingredient.

In such medicament combinations the steroid 3 is preferably selectedfrom among prednisolone, prednisone, butixocortpropionate, RPR-106541,flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone,mometasone, ciclesonide, rofleponide, ST-126, dexamethasone,(5)-fluoromethyl6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11[beta]-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothionate,(5)-(2-oxo-tetrahydro-furan-3S-yl)6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothionate,and etiprednol-dichloroacetate (BNP-166), optionally in the form of theracemates, enantiomers or diastereomers thereof and optionally in theform of the salts and derivatives thereof, the solvates and/or hydratesthereof.

In particularly preferred medicament combinations the steroid 3 isselected from the group comprising flunisolide, beclomethasone,triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,rofleponide, ST-126, dexamethasone, (S)-fluoromethyl6α,9α-difluoro-1Ia-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothionate,(S)-(2-oxo-tetrahydro-furan-3S-yl)6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothionate,and etiprednol-dichloroacetate, optionally in the form of the racemates,enantiomers or diastereomers thereof and optionally in the form of thesalts and derivatives thereof, the solvates and/or hydrates thereof.

In particularly preferred medicament combinations the steroid 3 isselected from the group comprising budesonide, fluticasone, mometasone,ciclesonide, (S)-fluoromethyl6α,9α-difluoro-1Ia-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,A-diene-17β-carbothionate,and etiprednol-dichloroacetate, optionally in the form of the racemates,enantiomers or diastereomers thereof and optionally in the form of thesalts and derivatives thereof, the solvates and/or hydrates thereof.

Any reference to steroids 3 includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids 3 may be: alkali metalsalts, such as for example sodium or potassium salts, sulphobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furcates.

Optionally, the inhalation device according to the invention containsplural of doses of a medicament on powder form that contains beside onecompound of formula 1 additionally both, one of the betamimetics 2mentioned hereinbefore and one of the steroids 3 mentioned hereinbefore.

According to one aspect, there is provided an inhalation deviceaccording to the invention, wherein each blister contains apharmaceutical composition in powder form wherein the pharmaceuticalcomposition comprises one or more, preferably one, compound of formula1.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.It may sometimes seem appropriate to add finer excipient fractions withan average particle size of 1 to 9 μm to the excipients mentioned above.These finer excipients are also selected from the group of possibleexcipients listed hereinbefore. Finally, in order to prepare theinhalable powders according to the invention, micronised activesubstance I—, and optionally 2 and/or 3, preferably with an averageparticle size of 0.5 to 10 μm, more preferably from 1 to 6 μm, is addedto the excipient mixture. Processes for producing the inhalable powdersaccording to the invention by grinding and micronising and finallymixing the ingredients together are known from the prior art.

For the methods of preparing the pharmaceutical compositions in powderform reference may be made to the disclosure of WO 02/30390, WO03/017970, or WO 03/017979 for example. The disclosure of WO 02/30390,WO 03/017970, and WO 03/017979 is herby incorporated by reference intothe instant patent application in its entirety.

As an example, the pharmaceutical compositions according to theinvention may be obtained by the method described below.

First, the excipient and the active substance are placed in a suitablemixing container. The active substance used has an average particle sizeof 0.5 to 10 μm, preferably 1 to 6 μm, most preferably 2 to 5 μm. Theexcipient and the active substance are preferably added using a sieve ora granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1mm, most preferably 0.3 to 0.6 mm. Preferably, the excipient is put infirst and then the active substance is added to the mixing container.During this mixing process the two components are preferably added inbatches. It is particularly preferred to sieve in the two components inalternate layers. The mixing of the excipient with the active substancemay take place while the two components are still being added.Preferably, however, mixing is only done once the two components havebeen sieved in layer by layer.

If after being chemically prepared the active substance used in theprocess described above is not already obtainable in a crystalline formwith the particle sizes mentioned earlier, it can be ground up into theparticle sizes which conform to the above-mentioned parameters(so-called micronising).

Many modifications and variations of the invention falling within theterms of the following claims will be apparent to those skilled in theart and the foregoing description should be regarded as a description ofthe preferred embodiments of the invention only.

Many modifications and variations of the invention falling within theterms of the following claims will be apparent to those skilled in theart and the foregoing description should be regarded as a description ofthe preferred embodiments of the invention only.

It will be appreciated that the inhalation device of the presentinvention may be used in conjunction with a spiral wound element and/ora fixed or flexible wall separating a chamber containing unused blistersfrom a chamber that receives the used blisters. Such modifications areknown from the Applicant's own earlier European patent applications nos.07111998.6 and 07111996.0.

1. An inhaler comprising a housing to receive a strip having a pluralityof blisters, each blister having a breachable lid and containing a doseof medicament for inhalation by a user, an indexing wheel mounted in thehousing rotatable to drive a strip to sequentially move blisters intoalignment with a blister piercing member, a control element pivotallymounted to the housing and a drive mechanism configured to couple thecontrol element to the indexing wheel during part of the rotation of thecontrol element by a user so that the indexing wheel rotates togetherwith the control element.
 2. An inhaler according to claim 1, whereinthe control element rotates relative to the housing about an axis andthe drive mechanism comprises a coupling member in the housing forrotation about the same axis.
 3. An inhaler according to claim 2,wherein the control element and coupling member are connected so thatthey rotate together.
 4. An inhaler according to claim 1, wherein theindexing wheel is rotatably mounted to the coupling member.
 5. Aninhaler according to claim 4, wherein the coupling member includes ashaft having an axis coaxial with the axis of the control element, theindexing wheel being mounted on said shaft for rotation about said axis.6. An inhaler according to claim 4, wherein the coupling membercomprises a indexing wheel drive dog and the drive mechanism includesmeans to move, as the control element and coupling member are rotated,the indexing wheel drive dog into a position in which it cooperates withthe indexing wheel so that the indexing wheel rotates together with thecontrol element and the coupling member.
 7. An inhaler according toclaim 6, wherein the coupling member is formed from a resilient materialand said means for moving the indexing wheel drive dog into a positionin which it cooperates with the indexing wheel moves said indexing wheeldrive dog against a bias provided by said resilience.
 8. An inhaleraccording to claim 7, wherein the coupling member comprises a flangethat extends radially from one end of the shaft across one end of theindexing wheel.
 9. An inhaler according to claim 8, wherein the flangelies in a plane extending substantially at right-angles to the axis ofthe shaft.
 10. An inhaler according to claim 8, wherein the flangeincludes a flexible flange portion that resiliently bends or flexesrelative to the remaining portion of the flange about an axis extendingsubstantially at right angles to the axis of the shaft.
 11. An inhaleraccording to claim 10, wherein the flange has an arcuate cut-out regionconfigured such that the flexible flange portion is joined only to theremaining portion of the flange at each end.
 12. An inhaler according toclaim 11, wherein the flexible flange portion is hinged to the remainingportion of the flange at each end.
 13. An inhaler according to claims10, wherein the indexing wheel drive dog upstands from a surface of theflexible flange portion in a direction towards the indexing wheel. 14.An inhaler according to claim 13, wherein the means to move the indexingwheel drive dog into a position in which it cooperates with the indexingwheel so that the indexing wheel rotates together with the controlelement comprises a coupling member deflecting dog protruding from theflexible flange portion.
 15. An inhaler according to claim 14, whereinthe means to move the indexing wheel drive dog into a position in whichit cooperates with the indexing wheel also comprises an arcuate guidetrack in the housing, the arcuate guide track having a first guidesurface such that, when the coupling member is rotated in response torotation of the control element in a first direction, the couplingmember deflecting dog cooperates with the first guide surface to deflectthe flexible flange portion towards the indexing wheel so that theindexing wheel drive dog cooperates with the indexing wheel to rotatethe indexing wheel together with the coupling member.
 16. An inhaleraccording to claim 15, wherein the arcuate guide track is configuredsuch that the coupling member deflecting dog drops off the first guidesurface prior to rotation of the control element to its maximum extent,the resilience of the flexible flange portion causing it to return toits original undeflected state so that the indexing wheel drive dog nolonger cooperates with the indexing wheel, the indexing wheel nowremaining stationary during continued rotation of the control elementand coupling member to its maximum extent.
 17. An inhaler according toclaim 15, wherein the arcuate guide track comprises a second guidesurface such that, when the flange portion deflecting dog has droppedoff the first guide surface and the coupling member is rotated inresponse to rotation of the control element in a reverse direction, theflange portion deflecting dog cooperates with said second guide surfaceso that the flexible flange portion is deflected in the oppositedirection, away from the indexing wheel.
 18. An inhaler according toclaim 17, wherein the coupling member deflecting dog comprises a firstcooperating surface to engage the first guide surface of the arcuateguide track, and, a second cooperating surface to engage the secondguide surface of the arcuate guide track.
 19. An inhaler according toclaim 18, wherein the first and second guide surfaces of the arcuateguide track extend parallel to each other but spaced from each other inan axial direction.
 20. An inhaler according to claim 19, wherein thefirst and second guide surfaces have angled end regions such that thecoupling member deflecting dog rides up the angled end regions ontorespective guide surfaces.
 21. An inhaler according to claim 6, whereinthe indexing wheel comprises a plurality of vanes and the indexing wheeldrive dog contacts one of the vanes when the indexing wheel drive dog ismoved into a position in which it cooperates with the indexing wheel sothat the indexing wheel rotates together with the coupling member andthe control element.
 22. An inhaler according to claim 6, comprising alocking element to prevent rotation of the indexing wheel other thanduring cooperation of the indexing wheel drive dog with the indexingwheel.
 23. An inhaler according to claim 22, wherein the locking elementcomprises a cantilevered arm mounted in the housing and having its freeend biased against the indexing wheel, said free end of the cantileverarm cooperating with the indexing wheel so as to prevent rotation of theindexing wheel.
 24. An inhaler according to claim 23, wherein the freeend of the cantilevered arm is configured such that when the indexingwheel drive dog is moved towards the indexing wheel, further rotation ofthe coupling element causes the indexing wheel drive dog to engage thefree end of the cantilever arm and deflect it out of locking engagementwith the indexing wheel prior to cooperating with the indexing wheel torotate the indexing wheel.
 25. An inhaler according to claim 24, whereinthe indexing wheel drive dog disengages the free end of the cantileverarm when the indexing wheel drive dog moves away from the indexing wheelso that the free end of the cantilever arm moves back towards theindexing wheel to lock the indexing wheel in position.
 26. An inhaleraccording to claims 23, wherein the indexing wheel comprises a pluralityof vanes and the free end of the cantilever arm comprises a slot, theslot being configured to receive a tip of a vane when the free end ofthe cantilever arm is biased against the indexing wheel to lock theindexing wheel in position.
 27. An inhaler according to claim 26,wherein each vane comprises an enlarged head portion and the slot in thefree end of the cantilever arm is configured to receive said enlargedhead portion.
 28. An inhaler according to claim 23, comprising a chassisto locate a blister strip as it moves therethrough, the cantilever armextending from said chassis.
 29. An inhaler according to claim 1,comprising a coiled strip of blisters received within the housing andpassing around the indexing wheel.